In an effort to improve response rates of chemotherapy, taxanes have been combined with other cytotoxic agents such as antimetabolites. However, the use of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) and taxanes was recognised in in vitro studies, showing synergistic effects for the sequence of MTX followed by paclitaxel, and antagonism for exposure in the reverse order. A possible explanation might be an MTX-induced synchronisation of cells in the S phase of the cell cycle, after which cells are more susceptible for the cytotoxic action of taxanes. Clinical studies using this sequence were hampered by severe neutropenia and mucositis at relatively low doses of both drugs. As no pharmacokinetic interactions were observed, the excess of toxicity may have been due to sequence-dependent synergistic actions on bone marrow and mucosa. In contrast, and confusingly, in vitro studies on 5-fluorouracil (5-FU) and taxanes indicate that 5-FU preceeding or simultaneously given to paclitaxel impairs cytotoxicity as compared with paclitaxel monotherapy, while the reverse sequence results in additive or synergistic cytotoxicity. While almost all clinical studies have used the sequence of a taxane followed by 5-FU, various schedules appeared feasible and effective. The combination of a 5-FU analogue, capecitabine and taxanes was supported by in vitro data. A large phase III trial confirmed the feasibility and superior efficacy of this combination in breast cancer patients relapsing after an anthracycline. Conflicting results exist on the benefit of combining gemcitabine and taxanes in tumour cell lines. Although the accumulation of gemcitabine triphosphate (dFdCTP) in mononuclear cells was significantly higher with an increasing dose of paclitaxel, no pharmacokinetic interactions for both agents were noticed. A pharmacokinetic analysis of the gemcitabine-docetaxel combination therapy has not been published in detail. Despite numerous trials, so far no optimum schedule has been established. Regarding data on actually delivered dose intensities, a 2- or 3-weekly cycle seems favourable and feasible. However, possible severe pulmonary toxicity warrants cautious monitoring of patients treated with this combination. Different outcomes of preclinical and clinical studies reveal that combining two chemotherapeutic agents is not simply a matter of putting antitumour activities together. Drug interaction may result in synergism, not only of efficacy but also of toxic side-effects. Adding two drugs may also implicate antagonism in drug efficacy due to unwanted interference in cytotoxicity or pharmacokinetics. For agents acting at a specific phase of the cell cycle, the sequence of administration may determine the efficacy and toxicity of a combination therapy. Because of an observed discrepancy between in vitro data and clinical studies, we would like to emphasise the need for adequate dose-finding clinical trials together with pharmacokinetic data analysis before examining any new combination chemotherapy in more detail in phase II studies.

Antimetabolites, Combination chemotherapy, Pharmacokinetics, Sequence, Taxanes,
European Journal of Cancer
Department of Medical Oncology

Smorenburg, C.H, Sparreboom, A, Bontenbal, M, & Verweij, J. (2001). Combination chemotherapy of the taxanes and antimetabolites: Its use and limitations. European Journal of Cancer (Vol. 37, pp. 2310–2323). doi:10.1016/S0959-8049(01)00309-4